Does MHC Heterozygosity Promote IgA Plasmablast Diversity in the Gut?

Abstract

Abstract The diversity of protein antigens the adaptive immune system can respond to is governed by polymorphic major histocompatibility complex (MHC) molecules. Because MHC alleles are co-dominantly expressed, MHC heterozygosity should allow for a wider diversity of antigens to activate T cells. B cells present antigen via MHC molecules to T cells, and through the ensuing T cell interaction, differentiate into plasma cells. Because of this, MHC heterozygosity should result in the generation of a plasma cell pool able to generate antibodies that target a wider array of antigens. To investigate this claim, we compared B cell selection dynamics between homozygote and heterozygote MHC congenic mice within the germinal centers (GCs) of Peyer’s patches; the major secondary lymphoid tissues of the gut where plasma cells develop in response to the microbiota. I have observed differences in the distribution of GC B cells between the dark zone (DZ) and light zone (LZ) of GCs. Specifically, GC B cells in MHC heterozygotes are found in greater abundance in the LZ and lower abundance in the DZ compared the GC B cells from MHC homozygote mice, which suggests that B cells are more capable of interacting with T cells in MHC heterozygotes. MHC heterozygotes also have significantly higher abundance of GC-T FHcells in their Peyer’s patches. I have observed that MHC heterozygote mice show enhanced binding of IgA to SI-resident bacteria. Future experiments seek to sort-purify IgA-bound SI-resident bacteria from MHC heterozygotes and homozygotes for 16S analysis to determine if MHC heterozygotes bind a more diverse array of bacterial species. We will also perform IgH-sequencing to define the effect of MHC heterozygosity on repertoire diversity of plasma cell populations. Supported by grants from the NIH (R21AI142409, R01AII55887)